CRTH2 is a G protein-coupled chemoattractant receptor, expressed on Th2 cells, eosinophils, and basophils (Nagata et al., J. Immunol., 162:1278-1286, 1999; Hirai et al., J. Exp. Med., 193: 255-261, 2001).
Th2 polarization has been observed in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis (Romagnani, S., Immunology Today, 18: 263-266, 1997; Hammad et al., Blood, 98: 1135-1141, 2001). Th2 cells regulate allergic diseases by producing Th2 cytokines such as IL-4, IL-5 and IL-13 (Oriss et al., J. Immunol., 162: 1999-2007, 1999; Viola et al., Blood, 91:2223-2230, 1998; Webb et al., J. Immunol., 165: 108-113, 2000; Dumont, F. J., Exp. Opin. Ther. Pat., 12: 341-367, 2002). These Th2 cytokines directly or indirectly induce migration, activiation, priming and prolonged survival of effector cells, such as eosinophils and basophils, in allegic diseases (Sanz et al., J. Immunol., 160: 5637-5645, 1998; Pope et al., J. Allergy Clin. Immunol., 108: 594-601, 2001; Teran, L. M., Clin. Exp. Allergy, 29: 287-290, 1999).
Prostaglandin D2 (PGD2), a ligand for CRTH2, is produced from mast cells and other important effector cells in allergic diseases (Nagata et al., FEBS Lett., 459: 195-199, 1999; Hirai et al., J. Exp. Med., 193: 255-261, 2001). The activation of CRTH2 by PGD2 induces the migration and activation of Th2 Cells and eosinophils, suggesting that CRTH2 may play a pro-inflammatory role in allergic diseases (Hirai et al., J. Exp. Med., 193: 255-261, 2001; Gervais et al., J. Allergy Clin. Immunol., 108: 982-988, 2001). Therefore, antagonists which inhibit the binding of CRTH2 and PGD2 should be useful for the treatment of allergic diseases, such as, asthma, exercise induced asthma, allergic rhinitis, atopic dermatitis and allergic conjuncitivitis.
In addition, experimental evidence has demonstrated the contribution of eosinophils in sinusitis (Hamilos et al., Am. J. Respir. Cell and Mol. Biol., 15: 443-450, 1996; Fan et al., J. Allergy Clin. Immunol., 106: 551-558, 2000), and Churg-Strauss syndrome (Coffin et al., J. Allergy Clin. Immunol., 101: 116-123, 1998). In the tissues of these patients, mast cells can be observed to be colocalized with eosinophils (Khan et al., J. Allergy Clin. Immunol., 106: 1096: 1101, 2000). It is suggested that PGD2 production from mast cells induces the recruitment of eosinophils. Therefore, CRTH2 antagonists are also useful for the treatment of other eosinophil-related diseases such as Churg-Strauss syndrome and sinusitis. CRTH2 antagonists can be useful for the treatment of some basophil-related diseases such as basophilic leukemia, chronic urticaria and basophilic leukocytosis, because of the high expression of CRTH2 on basophils.
Thus, there is a need for the development of compounds with CRTH2 antagonistic activity for the treatment of CRTH2-mediated disorders or diseases.